In previous work [Acta Pharmaceutica, Suecica, 15, 382-388 (1978), published February 1, 1979] applicant S. Yolles and co-workers V. Morton and B. Rosenberg reported that composites of cis dichlorodiammine-platinum(II), abbreviated cis-Pta.sub.2 Cl.sub.2, with doxorubicin and cyclophosphamide in poly (lactic acid), (PLA), showed a substantial and unexpected improvement in the life span of mice, in comparison with composites containing only cis-Pta.sub.2 Cl.sub.2. Specifically, 64 mg of composite cis-Pta.sub.2 Cl.sub.2 -doxorubicin-cyclophosphamide per kg mouse could be tolerated whereas cis-Pta.sub.2 Cl.sub.2 is toxic at 7 mg/kg mouse.
This work was covered by U.S. application Ser. No. 859,766 filed Dec. 12, 1977, for "Controlled Release of Anticancer Agents from Biodegradable Polymers" in the name of Seymour Yolles.
Complexes of 5,8-dihydroxy-1,4 naphthoquinone with several metals (beryllium, cobalt, copper, nickel and zinc) have been reported and their thermal stabilities determined [refer R. S. Bottei and P. L. Gerace, J. Inorg. Nucl. Chem., 23, 245, (1961)]. This study reported an unsuccessful attempt to prepare a platinum metal compound with 5,8-dihydroxy-1,4-napthoquinone.
H. D. Coble and H. F. Holtzclaw, Jr., J. Inorg. Nucl. Chem., 36, 1049 (1974) reported the properties of chelate polymers of copper (II) with several hydroxyquinones, including 5,8-dihydroxy-1,4 napthoquinone, 1,4-dihydroxy-and 1,5-dihydroxy-9,10 anthraquinone and 6,11-dihydroxy naphthacenequinone.
More recently, C. G. Pierpont, L. C. Francesconi and D. M. Hendrickson, Inorg. Chem. 17, 3470 (1978) reported preparation and characterization of binuclear nickel (II) and copper (II) complexes bridged by the dianions of 5,8-dihydroxy-1,4-naphthoquinone, and 1,4-dihydroxy-and 1,5 dihydroxy-9,10 anthraquinones.
S. Cenini, R. Ugo and G. Lamonica, Jl. Chem. Soc [A], 1971, p. 416 reported the preparation of two different chelates, with benzoquinone, one being of the 2-olefinic type and the other an orthoquinone, by reaction with diphosphine PtCl.sub.2 (O).
M. Gonsalves, et al, Europ. J. Cancer, Vol. 14, p. 1185 (1978) discloses the preparation and therapeutic advantages of "Ouelamycin," a complex of doxorubicin (Adriamycin.RTM.) with iron having the formula: ##STR1##
Finally, the September, 1979, Am. Chem. Soc, Inorganic Abstracts,Abstract 169, of Papers advises that F. T. Greenaway and J. C. Dabrowiak studied the metal-binding properties of doxorubicin and the chemically related compound, daunomycin, for Cu (II), Zn (II), Mg (II), Co (II), Ni (II) and Fe (III) ions.
According to the spectroscopic data, the metals bind to the aglycone and, at least in the case of Cu (II), to the amine function of daunosamine.
The distinction between daunomycin and doxorubicin is seen from the following structural formula: ##STR2## wherein R=H for daunomycin and R=OH for doxorubin